Parvin-β Inhibits Breast Cancer Tumorigenicity and Promotes CDK9-Mediated Peroxisome Proliferator-Activated Receptor Gamma 1 Phosphorylation

Abstract

Parvin-β is a focal adhesion protein downregulated in human breast cancer cells. Loss of Parvin-β contributes to increased integrin-linked kinase activity, cell-matrix adhesion, and invasion through the extracellular matrix in vitro. The effect of ectopic Parvin-β expression on the transcriptional profile of MDA-MB-231 breast cancer cells, which normally do not express Parvin-β, was evaluated. Particular emphasis was placed upon propagating MDA-MB-231 breast cancer cells in three-dimensional culture matrices. Interestingly, Parvin-β reexpression in MDA-MB-231 cells increased the mRNA expression, serine 82 phosphorylation (mediated by CDK9), and activity of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARγ), and there was a concomitant increase in lipogenic gene expression as a downstream effector of PPARγ. Importantly, Parvin-β suppressed breast cancer growth in vivo, with associated decreased proliferation. These data suggest that Parvin-β might influence breast cancer progression.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

We thank Don Baldwin, Grace Straszewski, and Donna Wilson (Penn Microarray Core Facility) for the gene expression profiling, Colleen Brensinger for statistical analysis, Jonathan Katz for the KLF4 antibody, Xinghai Li, David Tucker, and Morris Birnbaum for the PGC-1α antibody and protein, and Mitch Lazar for the pMSCV_Pparγ2 construct and helpful reading of the manuscript. We thank members of the Rustgi and Lazar labs for helpful discussions.

This work was supported in part by NIH/NIDDK grant R01-DK056645 (to A.K.R. and C.N.J.), a grant from the National Colorectal Cancer Research Alliance/EIF (to A.K.R.), a grant from the Irving A. Hansen Foundation (to A.K.R.), a Pennsylvania Department of Health Fellowship in Basic Cancer Research from the American Association for Cancer Research (to C.N.J.), a Concept Award (W81XWH-04-1-0658) from the U.S. Department of Defense Breast Cancer Research Program (to C.N.J.), and in part by grants from the National Cancer Institute of Canada (with funds from the Terry Fox Run) and the Canadian Institutes of Health Research (both to G.E.H.). G.E.H. was a CIHR scholar. This study was also supported by the Penn Center for Molecular Studies in Digestive and Liver Diseases and its core facilities (Morphology, Molecular Biology, and Cell Culture) through NIH/NIDDK grant P30 DK50306, the Penn Diabetes and Endocrinology Research Center (NIH/NIDDK grant DK19525), and the Optical/Bioluminescence Core of the Penn Small Animal Imaging Facility (supported in part by NIH grant CA105008).